c-MYC has been recognized for three decades as a key oncogenic driver since the discovery of retroviral oncogenes, their normal cellular counterparts, and immediate early response genes that are activated in response to mitogenic factors. A large fraction of all human cancers have also been shown to contain c- MYC gene amplifications, including 100% of some hematologic tumors and up to 70% of all solid tumors. Genetically engineered tumors of multiple types have confirmed the profound roll of c-MYC in tumor initiation and progression, and down regulation of c-MYC expression has shown significant therapeutic effects in many GEMM tumor types. Unlike most successfully drugged disease-causing proteins, c-MYC does not participate directly in a cellular signaling cascade as a receptor, kinase, or other signal transduction element and the protein has no known enzymatic activity or other function suitable for small molecule binding. Due to the inherent difficulty in targeting protein-protein and protein-DNA binding interactions, c-MYC has remained undruggable by conventional approaches. RNAi is a modality that can overcome the challenges of drugging the c-MYC protein directly because RNAi targets and destroys messenger RNA in a sequence-specific manner, thus reducing target protein expression as a consequence of mRNA elimination. RNA duplexes dissolved in infusion media and systemically administered as free duplexes are ineffective as cancer therapeutic agents for three reasons: 1) rapid clearance from blood by renal filtration, 2) rapid degradation by ubiquitous nucleases in blood, and 3) lack of accumulation in tumor tissues. One approach to overcome all three of these therapeutic limitations is to develop clinically acceptable nanoparticle formulations to efficiently deliver RN to tumors in vivo. Lipid-based nanoparticles are the most well established clinical stage formulations due to their similarities to approved liposomal drug products. By focusing our research and development on tumor-bearing animals, we have developed both a novel lipid composition and manufacturing process that dramatically improves both efficacy and tolerability of LNPs for RNA delivery, while minimizing inflammatory effects. Thus, our c-MYC DsiRNA formulated in LNPs that mediate intratumoral delivery has the potential to yield a therapeutic response in up to 70% of all cancer patients and with an acceptable therapeutic index. In this application we seek to expand the therapeutic index of our experimental drug further, enabling it to be used in patients highly compromised by their disease state, prior therapies, or in the case of hepatocellular carcinoma patients, by underlying chronic liver disease. Project Description Page 6.